A novel NDUFS4 frameshift mutation causes Leigh disease in the Hutterite population

• Published in: American journal of medical genetics. Part A Vol. 173; no. 3; pp. 596 - 600
• Main Authors: Lamont, Ryan E., Beaulieu, Chandree L., Bernier, Francois P., Sparkes, Rebecca, Innes, A. Micheil, Jackel‐Cram, Candice, Ober, Carole, Parboosingh, Jillian S., Lemire, Edmond G.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2017
• Subjects: Brain mapping; Canada; Consanguinity; DNA Mutational Analysis; Electron transport; electron transport complex I; Energy metabolism; Ethnic Groups - genetics; Female; founder effect; Frameshift Mutation; Gene mapping; genes, recessive; Genetic Association Studies; genetic diseases, inborn; Genotype; Humans; Hutterite; Infant; Leigh disease; Leigh Disease - diagnosis; Leigh Disease - genetics; Magnetic Resonance Imaging; Male; Mitochondria; mitochondrial diseases; Mutation; NADH; NADH dehydrogenase; NADH dehydrogenase (ubiquinone); NADH Dehydrogenase - genetics; NDUFS4; Neurodegenerative diseases; Neuroimaging; Oligonucleotide Array Sequence Analysis; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Seizures; Siblings; subacute necrotizing encephalomyelopathy; Ubiquinone; United States; Hutterite; genetic diseases, inborn; mitochondrial diseases; Leigh disease; founder effect; NDUFS4; genes, recessive; subacute necrotizing encephalomyelopathy; electron transport complex I
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.37983

Leigh disease is a progressive, infantile‐onset, neurodegenerative disorder characterized by feeding difficulties, failure to thrive, hypotonia, seizures, and central respiratory compromise. Metabolic and neuroimaging investigations typically identify abnormalities consistent with a disorder of mitochondrial energy metabolism. Mutations in more than 35 genes affecting the mitochondrial respiratory chain encoded from both the nuclear and mitochondrial genomes have been associated with Leigh disease. The clinical presentations of five individuals of Hutterite descent with Leigh disease are described herein. An identity‐by‐descent mapping and candidate gene approach was used to identify a novel homozygous c.393dupA frameshift mutation in the NADH dehydrogenase (ubiquinone) Fe‐S protein 4 (NDUFS4) gene. The carrier frequency of this mutation was estimated in >1,300 Hutterite individuals to be 1 in 27. © 2017 Wiley Periodicals, Inc.